Crystalline form of (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide, preparation, and uses thereof
The present invention relates to a crystalline form of (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetr a-hydropyrazolo[1,5-a]pyrimi dine-3-carboxamide for inhibiting Btk, methods of preparation thereof and pharmaceutical compositions, and use of the crystalline form above in the treatment of a disease, or in the manufacturing of a medicament for the treatment of a disease.
1. A chiral acid salt of Formula (Id):
wherein R 1 is methyl, benzyl, 4-methoxybenzyl, or tert-butyloxycarbonyl; and
the chiral acid is L-malic acid, D-malic acid, L-mandelic acid, D-mandelic acid, L-camphorsulfonic acid, D-camphorsulfonic acid, L-tartaric acid, D-tartaric acid, L-DBTA, D-DBTA, L-DTTA, or D-DTTA.
2. The chiral acid salt of claim 1 , wherein the chiral acid is L-DBTA.
3. A method for preparing a chiral acid salt of Formula (Id), comprising reacting a compound of Formula (Ic) with a chiral acid to provide the chiral acid salt of Formula (Id),
wherein:
R 1 is hydrogen, methyl, benzyl, 4-methoxybenzyl, or tert-butyloxycarbonyl; and
the chiral acid is L-malic acid, D-malic acid, L-mandelic acid, D-mandelic acid, L-camphorsulfonic acid, D-camphorsulfonic acid, L-tartaric acid, D-tartaric acid, L-DBTA, D-DBTA, L-DTTA, or D-DTTA.
4. The method of claim 3 , wherein R 1 is tert-butyloxycarbonyl.
5. The method of claim 4 , further comprising deprotecting the tert-butyloxycarbonyl group to provide a chiral acid salt of Formula (Id) wherein R 1 is hydrogen; and
reacting the chiral acid salt of Formula (Id) wherein R 1 is hydrogen with acryloyl chloride to provide Compound 1
((S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimi dine-3-carboxamide) having the structure:
6. A method for preparing a pharmaceutical composition comprising Compound 1, comprising mixing Compound 1 with a pharmaceutically acceptable excipient, wherein Compound 1 is prepared according to the method of claim 5 .
7. The method of claim 5 , wherein reacting the compound of Formula (Ic) with the chiral acid takes place in MeOH/H 2 O (about 3/1 by volume), EtOH/H 2 O (about 6/1 by volume), n-BuOH/H 2 O (about 6/1 by volume), EtOH, THF/H 2 O (about 1/1 by volume), or CH 3 CN/H 2 O (about 1/1 by volume).
8. The method of claim 7 , wherein reacting the compound of Formula (Ic) with the chiral acid takes place in CH 3 CN/H 2 O (about 1/1 by volume) or in in MeOH/H 2 O (about 3/1 by volume).
9. The method of claim 3 , wherein the chiral acid is L-DBTA.
10. The method of claim 9 , wherein reacting the compound of Formula (Ic) with the chiral acid takes place in MeOH/H 2 O (about 3/1 by volume), EtOH/H 2 O (about 6/1 by volume), n-BuOH/H 2 O (about 6/1 by volume), EtOH, THF/H 2 O (about 1/1 by volume), or CH 3 CN/H 2 O (about 1/1 by volume).
11. The method of claim 10 , wherein reacting the compound of Formula (Ic) with the chiral acid takes place in CH 3 CN/H 2 O (about 1/1 by volume) or in in MeOH/H 2 O (about 3/1 by volume).
12. A method for preparing a chiral acid salt of Formula (Id), comprising reacting a compound of Formula (Ic) with a chiral acid to provide the chiral acid salt of Formula (Id),
wherein:
R 1 is hydrogen and the chiral acid is L-DBTA; and
the method further comprises reacting the chiral acid salt of Formula (Id) with acryloyl chloride to provide Compound 1
((S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimi dine-3-carboxamide) having the structure:
13. The method of claim 12 , wherein reacting the compound of Formula (Ic) with the chiral acid takes place in MeOH/H 2 O (about 3/1 by volume), EtOH/H 2 O (about 6/1 by volume), n-BuOH/H 2 O (about 6/1 by volume), EtOH, THF/H 2 O (about 1/1 by volume), or CH 3 CN/H 2 O (about 1/1 by volume).
14. The method of claim 13 , wherein reacting the compound of Formula (Ic) with the chiral acid takes place in CH 3 CN/H 2 O (about 1/1 by volume) or in in MeOH/H 2 O (about 3/1 by volume).
15. The method of claim 12 , wherein reacting the chiral acid salt of Formula (Id) with acryloyl chloride takes place in a mixture of CH 3 CN and water in the presence of NaHCO 3 .
16. A method for preparing a pharmaceutical composition comprising Compound 1, comprising mixing Compound 1 with a pharmaceutically acceptable excipient, wherein Compound 1 is prepared according to the method of claim 12 .